Our previous studies have shown that angiotensin II increases carbonic anhydrase activity both in vitro and in vivo. In this study we investigated in vitro the effect of angiotensin II on carbonic anhydrase I and II from erythrocytes and on arteriolar vascular smooth muscle carbonic anhydrase I. We also studied in vitro and in vivo the effect of angiotensin II receptor blockers (irbesartan and candesartan) on purified carbonic anhydrase I and II, on vascular smooth muscle carbonic anhydrase I and on arterial blood pressure in humans and in animals. In vitro results showed that angiotensin II is a direct and stronger activator of carbonic anhydrase I than II. Angiotensin II receptor blockers reduced mainly carbonic anhydrase I activity and completely antagonized the activating effect of angiotensin II both on purified and on vascular smooth muscle carbonic anhydrase I. Our in vivo experiments showed that irbesartan and candesartan are powerful inhibitors of carbonic anhydrase I both in erythrocytes (in humans) and in vascular smooth muscles (in animals). In humans, irbesartan and candesartan progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive reduction of erythrocyte carbonic anhydrase I activity. We believe that angiotensin II could have a dual mechanism of action: (1) angiotensin interacting with its receptor to form a stimulus-receptor complex; (2) the same stimulus directly acts on the carbonic anhydrase I isozyme (which might be coupled with angiotensin II receptors), ensuring an adequate pH for stimulus-receptor coupling for signal transmission into the cell and hence vasoconstriction.